This invention relates to methods for ameliorating allergic immune responses. Particularly, according to this invention, natural or recombinant gamma interferons are administered within a predetermined temporal period prior to suppress a patient's allergic immune response.
Allergy is a hypersensitivity or altered reactivity to an antigen (allergen) that can result in pathologic reactions upon the exposure of a sensitized host to that particular antigen. Although the mechanisms involved in the induction and control of allergic reactions are not completely understood, they have been classified into four types. These include immediate hypersensitivity reactions (Type I), toxic effects of anticell and antitissue antibodies (Type II), toxic effects of complexes between antibody and antigen (Type III), and delayed hypersensitivity (cellmediated) reactions (Type IV).
In Type I, or immediate-type reactions, a variety of immunologic mechanisms may operate, but it is generally believed that they have a mediation pathway that involves the release of pharmacologically active substances from mediator cells. The antibody which is responsible for immediate hypersensitivity belongs to the IgE class of immunoglobulin. IgE antibodies bind to receptors on mediator cells such as mast cells and basophils. Once the IgE antibody is bound to the receptor, an allergen may bind to the antibody, causing the mediator cell to release granules which contain the pharmacologically active substances which lead to an allergic response.
These immediate-type reactions are triggered primarily by ingestants (foods and drugs), injectants (drugs and vaccines) and inhalants (airborne organic and inorganic substances). Symptoms include hay fever, food allergies, asthma, anaphylaxis, and urticaria. Delayed-type hypersensitivity may be triggered by the same kinds of antigens, however the increased reactivity to these specific antigens is mediated not by antibodies but by T-cells. This type of reaction is seen in some autoimmune diseases, and allergic contact dermatitis.
Current therapy of allergic hypersensitivity centers on avoiding offending allergens when feasible, use of appropriate drugs to counteract the symptoms, and immunotherapy. The first approach is not always practicable, and the second is only useful on a short-term basis. Additionally, the effectiveness of drugs such as antihistamines can be limited by side effects such as drowsiness and impaired mental acuity. Similarly, the use of corticosteroids may be limited by the appearance of local and/or systemic toxicity. The use of parenteral immunotherapy has been limited by the potential for systemic allergic reactions including anaphylaxis, as well as the amount of time to reach maintenance doses and the overall duration of the therapy.
As an alternative therapeutic approach, it has been suggested to interfere in vivo with the stimuli that act on the B lymphocytes that are essential for the production of IgE. The literature demonstrating this approach are inconclusive, because the studies involve inducing polyclonal responses rather than clearly antigen-specific IgE responses. Finkelman et al., J. Immunol 141:2335 (1988); Finkelman et al., J. Immunol. 137:2878 (1986); Katona et al., J. Immunol. 140:3206 (1988); Finkelman et al., J. Immunol 142:403 (1989).
Several in vitro studies have suggested that gamma interferon inhibits the production of IgE and thus may suppress an allergic response. See, for example, Coffman et al., J. Immunol. 136:949 (1986); Snapper et al., Science 236:944 (1987); Coffman et al., Immune Regulation by Characterized Polypeptides, Alan R. Liss, Inc. 523-532 (1987); DeFrance et al., J. Exp. Med. 165:1459 (1987); and Hudak et al., PNAS 84:4606 (1987). These in vivo studies share the same basic defect as the in vivo studies discussed above, in that the involve polyclonal responses rather than clearly antigen-specific IgE responses. For example, in an in vivo study, Finkelman et al., J. Immunol. 140:1022 (1988) demonstrate that gamma interferon may suppress the polyclonal, anti-immunoglobulin, immune response in mice stimulated by the injection of a goat antibody to mouse IgD, which by itself induces large increases in levels of serum IgE and increases in other immunoglobulins.
A few studies have proposed to treat allergies by administering gamma interferon to a patient in the course of an allergic response, however these studies are anecdotal, and either inconclusive or contradictory. Australian Patent Application AUA-48412/85 describes the administration of a gamma interferon to a patient with a food allergy. The patient received subcutaneous injections of 0.1.times.million I.U. of a gamma interferon formulation once a week for four weeks. It is stated that the patient's allergy was resolved after the first injection and this improvement lasted for six months after the last injection. The protocol does not indicate whether or how the patient's reaction to the antigen was challenged, or how recently before the treatment the patient had been exposed to the antigen.
PCT Application WO 87/01288 also claims the use of gamma interferon for treatment of allergies. This application appears to present the same study as Parkin et al., Br. Med. J. [Clin. Res.] 294: 1185 (1987). They describe the administration of 10 and 3,000 micrograms/M.sup.2 of gamma interferon to AIDS patients. While some of the patients found their allergic symptoms were apparently ameliorated, these patients also developed increased immediate and delayed hypersensitivity to common allergens. It is also indicated that other individuals in the study developed different allergic sensitivities over the course of the treatment. The observations are anecdotal, and the study provides little specific information on the challenge with the target antigen.
Two recent clinical trials of gamma interferon administration for allergies reveal contradictory data. In an anecdotal report, Boguniewicz et al., J. Allergy and Clin. Immunol 83:307 (100) (1989) disclose the treatment of 14 atopic dermatitis patients with gamma interferon. No placebo controls were included. Symptoms appeared somewhat ameliorated in some of the patients, serum IgE did not decrease, and spontaneous IgE production of peripheral blood lymphocytes decreased.
A more extensive published trial of gamma interferon with allergic patients is described in Li et al., J. Allergy and Clin. Immunol. 83:307 (543) (1989), which documents the double-blind, placebo-controlled trial of recombinant gamma interferon with forty-five adults having documented ragweed hay fever. This study seems to indicate that gamma interferon had little or no effect. There were no significant differences between the control and treated groups in mean weekly symptom scores, supplemental medication scores or hay fever scores, and preliminary inspection of the weekly IgE antibody measurements to crude ragweed extract suggested no marked differences among the groups.
In all of these studies, the dosages of gamma interferon and method and timing of its administration vary widely, as do the results. There remains a need for a treatment for allergies which avoids the disadvantages of the conventional methods and the inconsistencies of published methods of using gamma interferon, and yet provides effective treatment for allergic hypersensitivity.
It is an object of this invention to provide an effective therapy for patients suffering from allergies.
It is a further object of this invention to provide a means of preventing the occurrence of allergic reactions.
It is another object of this invention to increase the therapeutic efficacy of gamma interferon in vivo.